The proposed research will focus on a broad set of aims that center around the development and application of the nickel-catalyzed, silane-promoted reductive coupling of aldehydes and alkynes to generate allylic alcohols. Allylic alcohols are a common structural motif in many biologically and medicinally important compounds as well as versatile precursors for a broad array of organic reactions and catalytic processes. Fundamental studies will focus on understanding the mechanism and scope of this novel coupling process, and on developing new regioselective, diastereoselective, and enantioselective variants. An important aim of the proposed project period is the development of a new procedure for the direct assembly of a glycosylated macrocycle from a simple acyclic ynal, which will significantly simplify the preparation of carbohydrate- functionalized macrocycles. Applications in synthesis of natural and unnatural macrolides will be an important focus of the research plan. Naturally occurring macrolides make up a large family of biologically active macrocyclic natural products, and many members of this group possess carbohydrate appendages that greatly impact the molecular recognition events that are key in their biological activity. The antibiotic activities of members of this class are widely documented and clinically important, and many other modes of biological activity have been documented for this class of compounds. The structures specifically targeted include aigialomycin D, amphidinolide W, and 7-O-(alpha-glucosyl)-2,3-dihydrocineromycin B, and novel nickel-catalyzed reactions will be used as key steps in each of the syntheses. In addition to developing approaches to several macrolide natural products, our proposed method for assembly of glycosylated macrocycles will be used to access novel structures that will examined by the research group of David Sherman as substrates for cytochrome P450-catalyzed oxidations. This collaborative research will elucidate the substrate scope in cytochrome P450 oxidations and may lead to new compounds with potential as therapeutic agents.